Systemic diseases that are associated with pathogenic microorganisms or their toxins in the blood (e.g., septicemia) are a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases, and pathogenesis has been related in many cases to the release of a toxic outer membrane component termed endotoxin. However, gram-positive bacteria are an increasing cause of fatal infections. In addition, antibiotic resistance is becoming a major problem for all classes of antibiotics, and novel antibiotics are urgently needed.
Cationic peptides having antimicrobial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeast. Generally, these cationic peptides are thought to exert their antimicrobial activity on bacteria by interacting with the cytoplasmic membrane to form channels or lesions. In gram-negative bacteria, they interact with surface lipopolysaccharide (LPS) to permeabilize the outer membrane, leading to self promoted uptake across the outer membrane and access to the cytoplasmic membrane. Examples of antimicrobial peptides include indolicidin, defensins, cecropins, and magainins.